Matrix metalloproteases are a family of proteases responsible for degradation and remodeling of connective tissues. Members of this family of enzymes share a number of properties, including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology.
The matrix metalloprotease family includes interstitial collagenases, derived from fibroblasts/macrophages and neutrophils, which catalyze the initial and rate-limiting cleavage of native collagen types I, II, III and X.
Collagen, the major structural protein of mammals, is an essential component of the matrix of many tissues, for example, cartilage, bone, tendon and skin. Interstitial collagenases are very specific matrix metalloproteases which cleave collagen to give two fragments which spontaneously denature at physiological temperatures and therefore become susceptible to cleavage by less specific enzymes. As cleavage by the collagenase results in the loss of structural integrity of the target tissue, it is essentially an irreversible process and therefore a good target for therapeutic intervention.
In addition to interstitial collagenases, the matrix metalloprotease family of enzymes include two distinct, but highly related, gelatinases: a 72-kDa enzyme secreted by fibroblasts and a 92-kDa enzyme released by mononuclear phagocytes. These gelatinases are capable of degrading gelatins (denatured collagens), native collagen types IV and V, fibronectin and insoluble elastin.
The matrix metalloprotease family also includes stromelysins 1 and 2, which are capable of cleaving a broad range of matrix substrates, including laminin, fibronectin, proteoglycans and collagen types IV and IX in their non-helical domains.
Matrilysin (putative metalloprotease or PUMP) is a recently described member of the matrix metalloprotease family. Matrilysin is capable of degrading a wide range of matrix substrates including proteoglycans, gelatins, fibronectin, elastin, and laminin. Its expression has been documented in mononuclear phagocytes, rat uterine explants and sporadically in tumors.
Inhibitors of matrix metalloproteases are considered to provide useful treatments for arthritic diseases, bone resorption disease (such as osteoporosis), the enhanced collagen destruction associated with diabetes, periodontal disease, corneal ulceration, ulceration of the skin, and tumor metastasis. For example, the design and potential use of collagenase inhibitors is described in J. Enzyme Inhibition (1987), Vol. 2, pp. 1-22, and in Drug News & Prospectives (1990), Vol. 3, No. 8, pp. 453-458. Matrix metalloprotease inhibitors are also the subject of various patents and patent applications, for example, U.S. Pat. Nos. 5,189,178 (Galardy) and 5,183,900 (Galardy), European Published Patent Applications 0 438 223 (Beecham) and 0 276 436 (F. Hoffmann-La Roche), Patent Cooperation Treaty International Applications 92/21360 (Merck), 92/06966 (Beecham) and 92/09563 (Glycomed).